PROJECT SUMMARY/ABSTRACT The Gynecological Cancers Program includes 59 members (25 primary, 34 associate) from 15 departments, reflecting a 25% increase over the last 6 years. The program is led by Dr. Karen Lu (prevention studies and translational research), with co-leaders Dr. Anil Sood (basic science mechanistic studies and translational research) and Dr. Robert Coleman (developmental therapeutics and clinical trials). The major scientific goal of the program is to advance knowledge of gynecologic cancers and translate this knowledge to the cure and prevention of these diseases. To achieve this goal, the program has 4 themes that focus on 1) biology of therapeutic targets in gynecologic cancers; 2) developmental therapeutics; 3) health services research, quality improvement, and surgical outcomes; and 4) prevention and early detection. These, in turn, are paired with 4 specific aims. Specific Aim 1: To understand the mechanisms of tumor growth and metastasis in gynecologic cancers in order to identify novel molecular targets and inform future clinical studies; Specific Aim 2: To improve gynecologic cancer treatment by using a translational research platform that enables rapid clinical evaluation of biologics and immunotherapeutics, effect on molecular targets, and tumor adaptive responses; Specific Aim 3: To integrate patient-reported outcomes, quality improvement, and health services research into developmental therapeutics and surgical trials; Specific Aim 4: To reduce the incidence and mortality of gynecologic cancers by identifying innovative strategies for early detection and prevention. The annual direct cost peer-reviewed funding totals $4.4M, including the MD Anderson SPORE in Uterine Cancer, MD Anderson SPORE in Ovarian Cancer, a U01 EDRN-CVC for Early Detection of Ovarian Cancer, and U10 NRG Oncology Operations. Of the total peer-reviewed funding, $3.5M (80%) is from NCI grants. Since the last submission, the program has published 854 papers: 431 (50%) represent intra-programmatic collaborations, 216 (25%) represent inter- programmatic collaborations, and 619 (72%) represent inter-institutional collaborations. Thirty-eight percent of publications were in journals with IF >5, and 12% appeared in journals with IF >10, including Cancer Cell, J Clin Oncol, Lancet Oncol, and J Clin Invest. Program members utilize all 14 Shared Resources. During the last grant period, the program launched several high-impact initiatives, including the Ovarian Cancer Moon Shot and HPV Cancers Moon Shot. Accomplishments include the ?scope and score? algorithm to improve rates of achieving R0 (no gross residual disease) for ovarian cancer cytoreductive surgery and studies identifying mechanisms of adaptive response. A phase III clinical trial (GOG-0213) of bevacizumab added to standard chemotherapy followed by bevacizumab maintenance therapy showed improved overall survival in recurrent platinum-sensitive high-grade serous ovarian cancer. A CA125-based algorithm for ovarian cancer screening detected stage 1-2 disease in 70% of laparotomies, with a positive predictive value of 55%.